VACTERL Research Articles

High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% vs 44.1%; p = 0.0437), suggesting that non-genetic factors may play an important role in this subset of syndromic ARM cases. Within this cohort, we identified two individuals who carried de novo pathogenic frameshift variants in ADNP, two individuals who were homozygous for pathogenic variants in BBS1, and single individuals who carried pathogenic or likely pathogenic variants in CREBBP, EP300, FANCC, KDM6A, SETD2, and SMARCA4. The association of these genes with ARMs was supported by previously published cases, and their similarity to known ARM genes as demonstrated using a machine learning algorithm. These data suggest that ES should be considered for all individuals with syndromic ARMs in whom a molecular diagnosis has not been made, and that ARMs represent a low penetrance phenotype associated with Helsmoortel-van der Aa syndrome, Bardet-Biedl syndrome 1, Rubinstein-Taybi syndromes 1 and 2, Fanconi anemia group C, Kabuki syndrome 2, SETD2-related disorders, and Coffin-Siris syndrome 4.

Outcome of Newborns with Tracheoesophageal Fistula: An Experience from a Rapidly Developing Country: Room for Improvement.

This is a retrospective review of the medical electronic charts of patients with TEF that were followed at Sidra Medicine in the state of Qatar. The review included the patients who were operated upon in the period of 2011-2021 but continued to follow at our institution in the period of 2018-2021. Demographic data, associated anomalies, preoperative, operative, and postoperative courses, and growth parameters were collected. A total of 35 patients with TEF (24 males and 11 females) were collected. 49% were full term. We identified seven patients (20%) with isolated TEF, TEF with VACTERL association in 29% of our patients, other chromosomal anomalies in 17%, or associated with other anomalies (not related to VACTERL) in 34% of the patients. The majority of the patients (94%) were of type C-TEF (TEF with esophageal atresia-EA/TEF). All patients were operated except for one patient who died at 2 days of life due to cardiac complications. Median age at which surgery was performed was 2 days (range 1-270 days). Median follow-up was 32 months (range 7-115 months). Immediate postoperative complications were encountered in eleven patients (33%) and included anastomosis leak in 12%, air leak in 6%, sepsis in 6%, chylothorax in 3%, vocal cord palsy and fistula recurrence (combined) in 3%, and failure of TEF closure in 3% of the patients. Long-term respiratory complications were encountered in 43% of our patients. Long-term gastrointestinal complications included gastroesophageal reflux (GERD) in 63%, dysphagia in 31%, and anastomotic stricture in 34% of the patients. Growth was affected in around a quarter of the patients at 6 months after surgery and 22% at 12-month assessment postoperatively. While only five patients died at our institution, only one was directly related to failure of TEF closure and postoperative complications. This descriptive study reports the clinical outcome of TEF from a rapidly developing country. The distribution of the patients' characteristics and postoperative complications was almost comparable to those from developed countries. This study would aid in addressing the prognostic factors and establishment of evidence-based management pathways of newborns with TEF to improve the clinical outcome in our center and other pediatric tertiary centers in developing countries.

Challenges in prenatal diagnosis of foetal anorectal malformation and hydrocolpos – Case report

and importance: Foetal hydrocolpos and anorectal malformation are difficult to diagnose prenatally due to abundance of differential diagnoses. This case report presents the challenges of diagnosing such disorders. A G3P2A0 woman came at 32 weeks of pregnancy with a referral for foetal ovarian cyst. Ultrasound revealed a singleton breech pregnancy, estimated foetal weight 3528g. A septate abdominal cyst measuring 11.31×7.17 cm and polyhydramnios were present. Elective caesarean section delivered a female baby weighing 2820g and measuring 43 cm. Neonatal examination revealed a right lateral suprapubic mass and a rectovestibular fistula. A sinoscopy revealed a suspected hydrocolpos. An abdominal hydrocolpos drainage was performed; a patent urachus and normal bilateral adnexa were present. Hydrocolpos is a rare congenital disorder due to distal obstruction of various etiologies. It may be mistaken with other pathologies, including fetal ovarian cysts. A genitourinary congenital abnormality may occur in conjunction with other abnormalities, including gastrointestinal tract anomalies. The presence of imperforate anus and/or fistula should alert the clinician of a possible association with VACTERL syndrome. Hydrocolpos is a rare congenital genitourinary disorder with various differential diagnoses. Simultaneous presence of other abnormalities is likely, with possible association to other syndromes.

Lower Extremity Malformations.

Lower Extremity Malformations.

Swallowing-related quality of life in children with oesophageal atresia: a national cohort study

Swallowing and feeding disorders are a major concern for children with oesophageal atresia (OA) after primary or staged OA repair. Primary OA repair is associated with higher rates of short-term complications in preterm infants with very low birth weight (VLBW) or extreme low birth weight (ELBW). On the other hand, primary repair may have the benefit of early commencement of oral feedings. We hypothesize that also in the medium-term, swallowing-related quality of life is better after primary oesophageal repair. We conducted a prospective cross-sectional study on swallowing quality in a national cohort of former VLBW and ELBW children with OA, using the structured paediatric swallowing quality of life (pedSWAL-QOL) questionnaire. Results were correlated with surgical approach and baseline clinical data. Principal component analysis of pedSWAL-QOL domains was performed. In total, 44 complete data sets of 78 children were available. The mean age of children was 8.5 years (SD = 7.4), and 23 children (52%) had primary OA repair. The overall median pedSWAL-QOL score was 2 (IQR = 0–3), representing a high swallowing-related quality of life, independent of surgical technique (p = 0.086). Children with a history of intracranial haemorrhage (ICH) (p = 0.002) and those with VACTERL association (p = 0.008) had significantly decreased enjoyment with eating. In addition, children with VACTERL association had problems to find suitable foods (p = 0.04). Conclusion: In this national cohort of VLBW and ELBW preterm-born children with OA, swallowing-related quality of life is good, mostly independent of initial surgery. Children with OA and ICH or VACTERL association may require more intense support with feeding.What is Known:• Dysphagia, resembling feeding and swallowing disorders, is common in children and adults with repaired oesophageal atresia. Nevertheless, dysphagia in children with oesophageal atresia decreases with age.• Parents of younger children suffer from increased anxiety and fear regarding eating and swallowing abilities of their children.What is New:• Swallowing-related quality of life in former preterm children with oesophageal atresia is good, independent of initial surgical approach (primary vs. staged repair), even in very low birth weight or extreme low birth weight infants. • Children suffering from VACTERL association or intracranial haemorrhage show decreased enjoyment with eating.

Difficult vascular access for hemodialysis in congenital bilateral absence of radial artery and probable VACTERL association: a case report

Isolated bilateral absence of radial artery in association with other congenital anomalies, together named VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) is a very rare phenomenon. We report a patient, known to have VACTERL association, and who presented with ESRD. He was on hemodialysis and had been subjected to multiple failed tries at vascular access due to congenital bilateral absence of radial arteries and other vascular anomalies. This case report highlights hemodialysis options in congenital bilateral absence of radial artery and probable VACTERL association showing superiority of arteriovenous fistula despite its accompanying complications.
 Key words: VACTERL; Abnormalities, Multiple / classification; Kidney / abnormalities; Limb Deformities, Congenital; Bilateral absent radial artery; Hemodialysis; AV fistula, Failure; AV fistula, Complications
 Abbreviations: VACTERL - Vertebral defects, Anal atresia, Cardiac defects, Tracheo-esophageal fistula, Renal anomalies, and Limb abnormalities; AVF - Arteriovenous fistula; ESRD - End-stage renal disease; AVG - Arteriovenous graft; CVC - Central venous catheter
 Citation: Kareem G, Mahbuba W. Difficult vascular access for hemodialysis in congenital bilateral absence of radial artery and probable VACTERL association: a case report. Anaesth. pain intensive care 2022;26(3):559-562.
 DOI: 10.35975/apic.v26i4.1966
 Received: June 05, 2022; Reviewed: June 12, 2022; Accepted: June 17, 2022

Spondylocostal Dysostosis with Anal Atresia and Urogenital Anomalies in a Young Infant: First Case Entity of Casamassima-Morton-Nance Syndrome from Asia.

Casamassima-Morton-Nance syndrome (CMNS) includes a heterogeneous group of spondylocostal dysostosis along with anal atresia and genitourinary abnormalities. In 1981, Casamassima et al first described the syndrome in a fetus, and since then, only seven such cases have been reported so far. CMNS phenotype shows a significant clinical variability as documented in the reported cases. Etiology remains unknown yet, and it carries a poor prognosis. Here, we reported on a young female infant born out of nonconsanguineous marriage with normal karyotype and spondylocostal dysostosis, anal and genitourinary malformations suggesting CMNS. Ours is the eighth, and first case entity of CMNS reported from Asia as per the literature search. In our case, the additional feature of bilateral clubfoot has not been documented earlier in the literature. It extends the clinical spectrum of the syndrome and prompts us to consider it a close differential diagnosis to VACTERL (vertebral defects, anal atresia, cardiac malformations, tracheoesophageal fistula/esophageal atresia, renal anomalies, limb abnormalities) syndrome, which is commonly known and diagnosed. It also raises the question of whether cases of CMNS are being misdiagnosed as VACTERL syndrome due to its rarity.

In vitro fertilization outcomes in VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies and limb anomalies): report of 2 cases

ObjectiveTo report 2 cases of women with vertebral defects, anal atresia, cardiac defects, tracheaesophageal fistula, renal anomalies, and/or limb anomalies (VACTERL association) and the outcomes of their in vitro fertilization (IVF) cycles.DesignA case report. We obtained informed consent from both the patients for this case report.SettingOutpatient clinic at an academic hospital.Patient(s)Patient 1 was a 23-year-old woman with scoliosis, tethered spinal cord, tracheaesophageal fistula, duodenal atresia, and a common cloaca at birth. Patient 2 was a 36-year-old woman with dextrocardia, congenital heart disease, scoliosis, and an imperforate anus at birth.Intervention(s)Both the patients underwent IVF.Main Outcome Measure(s)Oocyte yield, oocyte quality, and number of embryos.Result(s)Patient 1 underwent 1 IVF cycle, with 16 oocytes retrieved, of which 6 were mature. However, during intracytoplasmic sperm injection, the oocytes were noted to be extremely fragile and degenerated immediately after sperm injection. No oocyte was fertilized. Patient 2 underwent 3 IVF cycles, and 2 oocyte retrievals, with a total of 7 oocytes under cryopreservation.Conclusion(s)Both the patients’ cases presented challenges due to aberrations in pelvic anatomy and poor IVF outcomes. There is a paucity of data regarding fertility outcomes and, specifically, oocyte quality in patients with vertebral defects, anal atresia, cardiac defects, tracheaesophageal fistula, renal anomalies, and/or limb anomalies association. Their care requires a multidisciplinary assessment, an individualized approach, and continued investigation of their IVF and fertility outcomes.

Does presence of a VACTERL anomaly predict an associated gynecologic anomaly in females with anorectal malformations?: A Pediatric Colorectal and Pelvic Learning Consortium Study

BackgroundVACTERL association is defined by the presence of 3 or more anomalies in any of the following systems: vertebral, anorectal, cardiac, trachea-esophageal, renal, or limb. This study hypothesized that the presence of VACTERL association would correlate with an increased risk of gynecologic anomalies in patients with anorectal malformation (ARM). MethodsThis study is a cross-sectional, retrospective analysis from the prospectively collected, multicenter registry of the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). The 834 female patients with ARM who were enrolled in the registry by January 1, 2020 were included in this study. The relationship of VACTERL association with presence of a gynecologic anomaly was evaluated with Fisher's exact test. The relationship of each VACTERL system with presence of a gynecologic anomaly was assessed in patients with cloaca, rectovestibular fistulas and rectoperineal fistulas. P-values reported were based on a 2-sided alternative and considered significant when less than 0.05. Results834 patients with ARM underwent VACTERL screening and gynecologic evaluation with the three most common subtypes being cloaca (n = 215, 25.8%), rectovestibular fistula (n = 191, 22.9%) and rectoperineal fistula (n = 194, 23.3%). A total of 223 (26.7%) patients with ARM had gynecologic anomalies. VACTERL association was seen in 380 (45.6%) of patients with ARM. Gynecologic anomalies were present in 149 (39.1%) vs. 74 (16.3%) of subjects with vs. without VACTERL association (p < 0.001). VACTERL association did not significantly increase the risk of gynecologic anomaly in patients with cloaca and VACTERL (n = 88, 61.5%) vs. cloaca without VACTERL (n = 39, 54.2% p = 0.308). VACTERL association increased the risk of gynecologic anomalies in patients with rectoperineal fistulas (n = 7, 14.9% vs n = 9, 6.1% p = 0.014) and rectovestibular fistulas (n = 19, 31.1% vs. n = 13, 10.0% p<0.001). In patients with ARM who had a VACTERL association, when one of the associated anomalies was renal, there was an even higher risk of having an associated gynecologic anomaly (n = 138, 44.2% vs. n = 85, 16.3% p<0.001). ConclusionsVACTERL association in patients with rectoperineal and rectovestibular fistulas correlates with an increased risk of gynecologic anomalies. The presence of VACTERL associated findings, especially renal, should prompt a thorough evaluation of the gynecologic system. Level of evidenceIII. Retrospective comparative study

Abstract 1998: A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies

Abstract Purpose: There is emerging evidence that children with multiple congenital anomalies have a higher risk of developing cancer compared to unaffected children. However, there have been few population-based estimates of cancer risk among children with well-described patterns of recurrent multiple congenital anomalies (MCAs). VACTERL association is one such pattern that is defined by the presence of ≥3 of the following in the absence of a genetic diagnosis: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal, and limb anomalies. VACTERL occurs in approximately 5% of children with Fanconi anemia (FA), a known cancer predisposition syndrome. In spite of this, there are no population-based estimates of cancer risk in children with VACTERL. Therefore, we investigated if VACTERL confers an elevated risk of pediatric cancer by examining a birth cohort of &amp;gt;7 million children from three U.S. states (Texas, North Carolina, and Oklahoma) for the period 1997-2013. Methods: Demographic and diagnostic data from birth certificates, birth defects registries, and cancer registries were linked in each state and pooled for analysis. For this analysis, children with chromosomal anomalies were excluded. We used Cox proportional hazards models to evaluate the risk of cancer before 19 years of age in three birth defect groups: (1) VACTERL; (2) ≥3 major anomalies but not VACTERL; and (3) 1 to 2 major anomalies. A hazard ratio (HR) and 95% confidence interval (CI) was calculated in each group for: (1) overall cancer risk and (2) risk of embryonal tumors (e.g., neuroblastoma, medulloblastoma, hepatoblastoma) based on reported associations between birth defects and these pediatric cancers. Results: In our cohort of 7,767,786 births, we identified: 2,090 children (0.02%) with VACTERL; 32,558 children with ≥3 non-VACTERL defects; and 201,871 children with 1 to 2 defects. Respectively, these three groups had 10, 167, and 684 cases of cancer. Compared to children without birth defects, children with VACTERL (HR=3.9, 95% CI: 2.1 - 7.2), ≥3 non-VACTERL defects (4.2, 3.6 - 4.9), and 1 to 2 defects (2.7, 2.5 - 2.9), were all more likely to develop cancer. Risk was higher for embryonal tumors among children with VACTERL (10.4, 4.7 - 23.1) than for those with ≥3 non-VACTERL defects (5.6, 4.2 - 7.4) or 1 to 2 defects (3.9, 3.4 - 4.5). Conclusion: In this population-based assessment, we demonstrated that children with VACTERL were more likely than other groups to develop cancer, particularly embryonal tumors, although the absolute cancer risk was &amp;lt;1%. Surprisingly, acute myeloid leukemia, a common malignancy among individuals with FA, was not diagnosed in any of the children with VACTERL, suggesting these associations are distinct from FA. These findings demonstrate that VACTERL subtypes and other recurrent MCAs may represent novel cancer predisposition syndromes. Citation Format: Alexander Renwick, Jeremy M. Schraw, Tania A. Desrosiers, Amanda E. Janitz, Michael E. Scheurer, Mark A. Canfield, Peter H. Langlois, Angela E. Scheuerle, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1998.

Terminal myelocystocele: Surgical management.

Background: The authors describe clinical and imaging findings, surgical technique, and outcomes in myelocystocele.Methods: We describe a surgical procedure performed in six patients, four males and two females, with myelocystocele treated at our hospital. We review the images obtained at the time of diagnosis and after surgery. The patients’ age range was 12–56 months and had undergone surgery for terminal myelocystocele between 2015 and 2020. All patients had a large lumbar mass covered with healthy skin and presented spontaneous movements at birth. Two patients presented VACTERL syndrome.Results: A watertight closure of the soft tissues was performed in all cases. None of the patients presented postsurgical complications, such as cerebrospinal fluid leak or infection. All the patients had undergone excision of the meningocele sacs, the tethering bands were lysed, and the filum was detethered. The mean follow-up period was 34 (12–56) months. A motor deficit was seen in 2 patients (33.3%).Conclusion: Prenatal diagnosis and early corrective surgical intervention are recommended to prevent deterioration in neurological function. VACTERL association is a common condition and should be investigated.

PULMONARY COMPLICATIONS OF ESOPHAGEAL DISEASE: ABOUT A CASE REPORT

TYPE: Late Breaking Case Report TOPIC: Pediatrics INTRODUCTION: The close anatomical relationship between the esophagus and the lung makes the latter vulnerable for esophageal diseases which are relatively common in children. CASE PRESENTATION: We report the observation of a 4-year-old girl with poly malformations suggestive of VACTERL syndrome. She underwent surgery on her first day of life for esophageal atresia with a tracheoesophageal fistula. At the age of 5 months, she developed a chronic cough and a recurrent pneumonia. The barium swallow study showed a massive supra carinal GERD, an anastomotic esophageal diverticulum and an early opacification of the bronchial tree evoking a GERD which floods the lungs or a tracheoesophageal fistula (figure). The pulmonary involvement on the thoracic CT scan was impressive with a tree-in-bud sign, parenchymatous condensations, atelectasis in retractile band, bronchiectasis and ground glass areas. she received proton pump inhibitor and anti inflammatory long term azithromycin treatment. The control barium swallow test objectified vanishing of the lung flooding. The outcome was marked by a recurrent wheezing requiring tretatment by inhaled corticosteroid. DISCUSSION: Aspiration pneumonitis is the main complication of esophageal diseases. The challenge is to determine its mechanism; is it GERD, tracheoesophageal fistula, esophageal stenosis or diverticulum as reported in this case. the objective of an early diagnosis is to not delay the appropriate treatment and to stabilize the respiratory function before irreversible damage occur, namely, bronchiectasis, bronchiolitis or lung fibrosis. CONCLUSIONS: Thus, clinical and radiological monitoring of the respiratory system in the context of esophageal disease is a crucial element to watch out for complications at an early stage. DISCLOSURE: Nothing to declare. KEYWORD: lung

Understanding of the transition to adult healthcare services among individuals with VACTERL association in Sweden: A qualitative study.

Current knowledge of transitional care from the perspective of individuals with congenital malformations is scarce. Their viewpoints are required for the development of follow-up programs and transitional care corresponding to patients’ needs. The study aimed to describe expectations, concerns, and experiences in conjunction with transfer to adult health care among adolescents, young adults, and adults with VACTERL association, (i.e. vertebral defects, anorectal malformations (ARM), cardiac defects (CHD), esophageal atresia (EA), renal, and limb abnormalities). Semi-structured telephone interviews were performed and analyzed with qualitative content analysis. Of 47 invited individuals, 22 participated (12 males and 10 females). An overarching theme emerged: Leaving the safe nest of pediatric health care for an unfamiliar and uncertain follow up yet growing in responsibility and appreciating the adult health care. The participants described expectations of qualified adult health care but also concerns about the process and transfer to an unfamiliar setting. Individuals who were transferred described implemented or absence of preparations. Positive and negative experiences of adult health care were recounted including being treated as adults. The informants described increasing involvement in health care but were still supported by their parents. Ongoing follow up of health conditions was recounted but also uncertainty around the continuation, missing follow up and limited knowledge of how to contact health care. The participants recommended information ahead of transfer and expressed wishes for continued health care with regular follow up and accessibility to a contact person. Based on the participants’ perspective, a transitional plan is required including early information about transfer and follow up to prepare the adolescents and reduce uncertainty concerning future health care. Meetings with the pediatric and adult team together with the patient and the parents are essential before transfer. Follow up should be centralized to centers with multi-professional teams well-experienced with the condition. Further studies are warranted to evaluate the transition process for adolescents and young adults with complex congenital health conditions.

Bacterial Sepsis among Children with Congenital Heart Disease in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia.

Bacterial Sepsis is a serious medical problem affecting children with Congenital Heart Disease (CHD). The pattern and factors predicting outcome of bacterial sepsis have not been studied in Africa. The study aimed to describe the pattern and outcome of bacterial sepsis among children with CHD in Tikur Anbessa Specialized Hospital (TASH). A cross-sectional study was carried out among children with CHD and sepsis at TASH between May 2017 and July 2020. Structured questionnaires were used for data collection. Statistical significance was set at P value < 0.05, and multivariable logistic regression was used to determine predictors. This study included 384 CHD children with sepsis. Proportion of culture proven bacterial sepsis was 17.1 % (66) (95% CI: 13.6-21.3). Coagulase negative staphylococcus aureus 7% (27), Staphylococcus aureus 4.4% (17) and Actinobacteria 1.8% (7) were the common isolated bacteriological agents. Death was documented in 25% (96) of study subjects. Down syndrome subjects were 2.4 times [aOR=2.416 (95%CI: 1.367-4.264)] more likely to die from sepsis. Those with associated comorbidities (Apert syndrome, Cerebral palsy, Chiari 2 malformation, Patau syndrome, Noonan syndrome, Congenital Rubella, Portal vein thrombosis, HIV, Scoliosis and VACTERL association) were 4.4 times more likely to die from sepsis [aOR=4.418 (95%CI: 1.617-12.072)]. Bacterial sepsis is a common problem among children with CHD. Gram positive bacteria were common causes. Down syndrome and other co morbidities predicted bacterial sepsis mortality. Blood culture and sensitivity tests are recommended to halt the high mortality seen in Down syndrome or those with co morbidities.

Prenatal Diagnosis and Outcome of Scimitar Syndrome: A Case Series of Six Patients.

Scimitar syndrome is a rare disease characterized by hypoplasia of the right lung and partial anomalous pulmonary venous drainage to the inferior vena cava. All cases with a prenatal diagnosis of scimitar syndrome with or without associated malformations in an 18-year period (2000–2018) in two large tertiary referral centers (University of Bonn and University of Cologne, Germany) were retrospectively reviewed for the intrauterine course and postnatal outcome. Six cases were diagnosed in the study period. All presented with hypoplasia of the right lung, right-sided mediastinal shift, and abnormal pulmonary venous drainage to the inferior vena cava. Systemic arterial blood supply to the right lung, albeit postnatally present in all cases, could not be detected prenatally. Major associated anomalies were present in all cases and included atrial septal defect (n = 5), coarctation (n = 3), diaphragmatic hernia (n = 2), and VACTERL association (n = 1). Half of the cohort died within 6 months after birth and all three survivors suffer from long-term pulmonary sequelae. The primary hint to the prenatal diagnosis of scimitar syndrome is the abnormal position of the heart in the chest. If searched for, abnormal venous drainage can be identified prenatally and confirms the diagnosis. The prognosis depends on the presence of associated major anomalies and the need for neonatal intervention.

EP404: Evidence supporting the pathogenicity of the NADSYN1 c.1717G>A (p.Ala573Thr) variant in individuals referred for clinical testing

Vertebral, cardiac, renal, and limb defects syndrome 3 (VCRL3; OMIM #618845) is an autosomal recessive multiple congenital anomaly syndrome caused by pathogenic variants in the NADSYN1 gene. NADSYN1 encodes a nicotinamide adenine dinucleotide (NAD) synthetase that is part of the de novo NAD synthesis pathway. Other genes involved in this pathway include HAAO and KYNU. Genetic variants in any of these genes result in reduced de novo NAD synthesis and cause congenital anomalies of the heart, kidney, and vertebrae. Of note, presence of these three features is also considered clinical evidence for vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association, which is often a diagnosis of exclusion (ie, other genetic conditions with overlapping features must be ruled out before assigning this diagnosis). The recommended approach for genetic testing in possible VACTERL patients is to either pursue a comprehensive testing option, such as exome or genome sequencing, or a panel approach with the most likely candidates. The NADSYN1 gene is included on a VACTERL Association and Related Disorders panel and several patients were noted to be homozygous for the NADSYN1 c.1717G>A (p.Ala573Thr) variant, thus providing additional evidence for both the pathogenicity and high carrier frequency of this change. To date, we have identified five patients who are homozygous for the NADSYN1 (NM_018161.4) c.1717G>A (p.Ala573Thr) variant. One patient was identified through targeted testing, one through testing with the VACTERL Association and Related Disorders panel, and three through exome sequencing. The first four cases were from pregnancies evaluated for the differential diagnosis of VACTERL association via panel testing or exome sequencing. All four fetuses were reported to have cardiac malformation and segmental vertebral anomalies. Parental data was available for three of the four fetuses, and all parents tested were heterozygous for the NADSYN1 c.1717G>A (p.Ala573Thr) variant. All cases denied consanguinity. In contrast to the severe and early onset features of the other four patients identified, the targeted testing case was an adult patient who previously had the NADSYN1 c.1717G>A variant identified in a research study. This individual was noted to have cardiac defects, vertebral defects, and short stature. This variant is relatively common in non-Finnish Europeans with an allele frequency of 0.15% in the gnomAD v2 dataset. Five patients from four families with VCRL3 have been described in the literature. Of these patients, three had the c.1717G>A variant: two homozygous siblings and one compound heterozygote with a loss of function variant on the opposite allele. Parental sequencing data confirmed the biallelic variants in all reported patients. In addition, yeast model functional studies performed by Szot and colleagues demonstrated that the p.Ala573Thr change diminished NAD synthetase activity and reduced yeast viability, consistent with a loss of function mechanism. Taken together, although the NADSYN1 c.1717G>A (p.Ala573Thr) has a relatively high minor allele frequency, there is sufficient evidence for this variant to be classified as pathogenic using ACMG/AMP variant classifications and internal variant interpretation guidelines. The NADSYN1 c.1717G>A (p.Ala573Thr) variant should be interpreted as pathogenic given the 5 additional homozygous patients and parental segregation data presented here. Additionally, the diagnosis of VCRL3 in an adult patient suggests that although penetrance for NAD deficiency is complete, variable expressivity is observed and could be explained by other genetic or non-genetic factors modulating disease severity. Given the high population frequency of this variant, genetic testing for VACTERL association should always include evaluation of NADSYN1 to consider VCRL3 in the differential diagnosis.

EP475: Long-term follow-up on fetuses diagnosed in second trimester with isolated single umbilical artery and normal chromosomal microarray

Fetuses diagnosed with isolated Fetal Single Umbilical Artery (iSUA), defined when no additional anatomical abnormalities are detected, and are not associated with significantly increased risk for chromosomal anomalies. However, information on their long-term outcome is lacking. The objective of the current study is to examine the long-term outcomes of fetuses diagnosed in second trimester with iSUA and normal chromosomal microarray assay (CMA). A retrospective review was conducted including all cases referred to our center with iSUA and a normal CMA between 2016 to 2020 (study group). Obstetrical and postnatal medical files were reviewed. Parents were contacted for a structured interview including neurodevelopment development assessment using Ages & Stages Questionary-3 (ASQ-3). A total of 282 cases of iSUA were referred for prenatal counseling, 48 (17%) opted to perform an invasive diagnostic test. The final study group consisted of 45 patients. Pregnancy follow-up was conducted in a dedicated clinic and included prenatal echocardiography and a 3rd-trimester malformation scan. Post-natal follow-up range was 3±2.2 years. In 9 (20%) cases of the study group additional findings were detected downstream: 4 (45%) cases prenatally (esophageal atresia, congenital anomaly of kidney, Severe Intrauterine growth retardation, and VACTERL association). Five cases (55%) showed abnormal findings only postnatally: 3 cases (6.6%) with malformations (brachial cyst and polydactyly and GLI1 pathogenic variant, sacral malformation and heterotopia due to FLNA pathogenic variant, and one case with coloboma - in assessment). 2 cases (4.4%) with functional abnormalities (one with recurrent meningitis and strabismus and one with prematurity and diplegic cerebral palsy) all being under evaluation. Two (4%) additional cases were diagnosed with neurodevelopment delay. ASQ-3 scores in all other study group participants were in the normal range. Fetuses diagnosed with iSUA and normal CMA in the second trimester are at increased risk for anatomical and functional complications including single-gene disorders. Additional findings might be disclosed in later stages of pregnancy but more importantly – can evolve postnatally only. Therefore, an extra risk should be given to the counselee and exome analysis should be considered. Further studies are required to reinforce this data

Reporte de caso: Recién nacido con asociación VACTERL y traqueomalacia

VACTERL association is the non-random co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, renal and limb congenital malformations, and in addition may be associated with tracheomalacia. The aim of this report is to describe the presence of congenital malformations in a case of VACTERL and tracheomalacia association. We report the case of a newborn whose adolescent mother reported occasional alcohol consumption. At birth he received CPR with orotracheal intubation and was diagnosed with VACTERL association and sepsis, which was treated with antibiotics. Since birth he presented stridor and at one month of life, the diagnosis of tracheomalacia was confirmed by laryngoscopy. We conclude that VACTERL association in a newborn may be accompanied by some other malformation, such as tracheomalacia, and its detection is essential for proper management and prevention of complications.

Long-term urology outcomes of anorectal malformation

Urological problems are a recognised feature of anorectal malformation (ARM). Previous assumptions of favourable long-term urinary outcomes are being challenged. We hypothesised that urinary tract problems are common in ARM and frequently persist into adulthood. We retrospectively reviewed long-term renal and bladder outcomes in ARM patients. Patients with ARM born between 1984-2005 were identified from electronic hospital databases. Their case notes were reviewed. Renal outcomes included serum creatinine and the need for renal replacement therapy. Bladder outcomes included symptom review, bladder medication, need for intermittent catheterisation, videourodynamics and whether the patient had undergone augmentation cystoplasty. RESULT (TABLE 1): The case notes of 50 patients were reviewed. The median age at last follow up was 18 years (range 12-34 years). The level of fistula was noted to be high in 17 patients, intermediate in eight, and low in 10. Four had cloaca. Congenital urological abnormalities were present in 25 (50%). An abnormal spinal cord was present in 22 (44%) patients. VACTERL association occurred in 27 (54%). Chronic kidney disease stage II or above was found in 14 (28%) patients, of whom four required a renal transplant. Abnormal bladder outcomes were found in 39 (78%) patients. Augmentation cystoplasty with Mitrofanoff had been performed in 12. Of those who had not undergone cystoplasty, 17 had urinary symptoms, including urinary incontinence in 12. Of the 39 patients with abnormal bladder outcome, 19 (49%) did not have a spinal cord abnormality. There was no significant statistical association between level of ARM and abnormal renal outcome or presence of bladder abnormality. Adverse renal and bladder outcomes are common in our cohort of young people with ARM with a significantly higher incidence compared with current literature. We did not demonstrate an association between level of ARM or presence of spinal cord anomaly with persistent bladder problems. Congenital urological anomalies are more common in those who later have an abnormal renal outcome. Although this difference is statistically significant, one fifth of patients born with anatomically normal upper tracts develop reduced renal function, implying an important acquired component. Bladder problems and reduced renal function affect a significant proportion of young adults with ARM. Neither adverse outcome is reliably predicted from ARM level, congenital urological anomaly or spinal cord anomaly. We advise continued long-term bladder and kidney follow-up for all patients with ARM.

Cannabinoid and substance relationships of European congenital anomaly patterns: a space-time panel regression and causal inferential study.

With reports from Australia, Canada, USA, Hawaii and Colorado documenting a link between cannabis and congenital anomalies (CAs), this relationship was investigated in Europe. Data on 90 CAs were accessed from Eurocat. Tobacco and alcohol consumption and median household income data were from the World Bank. Amphetamine, cocaine and last month and daily use of cannabis from the European Monitoring Centre for Drugs and Drug Addiction. Cannabis herb and resin Δ9-tetrahydrocannabinol concentrations were from published reports. Data were processed in R. Twelve thousand three hundred sixty CA rates were sourced across 16 nations of Europe. Nations with a higher or increasing rate of daily cannabis use had a 71.77% higher median CA rates than others [median ± interquartile range 2.13 (0.59, 6.30) v. 1.24 (0.15, 5.14)/10 000 live births (P = 4.74 × 10−17; minimum E-value (mEV) = 1.52]. Eighty-nine out of 90 CAs in bivariate association and 74/90 CAs in additive panel inverse probability weighted space-time regression were cannabis related. In inverse probability weighted interactive panel models lagged to zero, two, four and six years, 76, 31, 50 and 29 CAs had elevated mEVs (< 2.46 × 1039) for cannabis metrics. Cardiovascular, central nervous, gastrointestinal, genital, uronephrology, limb, face and chromosomalgenetic systems along with the multisystem VACTERL syndrome were particularly vulnerable targets. Data reveal that cannabis is related to many CAs and fulfil epidemiological criteria of causality. The triple convergence of rising cannabis use prevalence, intensity of daily use and Δ9-tetrahydrocannabinol concentration in herb and resin is powerfully implicated as a primary driver of European teratogenicity, confirming results from elsewhere.